PROJECT SUMMARY: Zika virus (ZIKV) has recently emerged in the Western Hemisphere, causing a massive, currently ongoing outbreak in South America. ZIKV appears to be neurotropic, with microcephaly and other fetal brain defects being among the most serious outcome of infection. Currently, there are no vaccines or specific antiviral treatments for ZIKV; therefore understanding its pathogenesis in humans is a high priority. ZIKV is phylogenetically related to other flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV). It has recently been proposed that the presence of antibodies against DENV can enhance ZIKV infection through a phenomenon known as antibody-dependent enhancement (ADE). In the continental United States, DENV does not currently circulate; however, WNV has been circulating in the US for over 15 years, causing annual outbreaks of infection. Thus, we hypothesize that antibodies against WNV enhance ZIKV infection. To test this hypothesis, we will 1) determine and characterize the cross reactivity of WNV antibodies with ZIKV, and 2) evaluate the antibody-dependent enhancement in vitro and ex vivo. Our studies will provide much needed insight into understanding how prior infection with WNV could enhance susceptibility to ZIKV.